Our research group has been examining stress disorders and gender differences for over 20 years and discovered a variety of biological abnormalities and pharmacotherapies. Responses to stress and to cocaine cues strongly affect the propensity to become dependent and to relapse after attaining abstinence and may differ in men and women. Gender differences in functional brain imaging responses to emotional stimuli and in the neuroendocrine response to stress are well documented. Our current fMRI work has shown that, in response to cocaine cues the anterior cingulate (AC) activates positively in cocaine dependent subjects compared to healthy controls. However, in response to stress, healthy controls activate the AC more than cocaine dependent individuals. This difference in AC activation is an important difference between cocaine cues and stressors as precipitants to cocaine use. Gender differences in these vulnerabilities may be related to different neural pathways and may form the basis for differences between genders in coping strategies and treatment outcome. A specific environmental vulnerability factor for gender differences in these neural pathways may be early life stress of physical and sexual abuse, which is a linking concept to the animal studies in this SCOR Center. In a sample of 25 male and 25 female healthy controls and 25 male and 25 female cocaine dependent subjects we will use blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) to measure brain activation in two imaging sessions on each subject. Each imaging session will measure the response to personalized stressful, cocaine cue and neutral audiotaped scripts. The specific aims are: (1) To assess gender differences in brain activation patterns in response to stress and cocaine cues in cocaine dependent and healthy subjects. (2) To examine gender differences in intrasubject variability on fMRI responses to stressful, cocaine cue and neutral audiotaped scripts. (3) To explore whether frontal brain activation in response to stress varies as a function of the presence or extent of early trauma and whether or not this effect is greater in women compared to men.